Current diabetes treatments have limited efficacy in addressing the risk of developing microvascular complication of diabetes such as diabetic retinopathy. Diabetic retinopathy (DR) is the most frequent cause of new cases of blindness among working-age adults. Despite intensive glycemic control, 80% of Type 2 diabetes patients will progress to DR within 15 years of disease onset. In addition, diabetic retinopathy develops in 70- 100% of individuals with Type 1 diabetes. The management of DR revolves around panretinal laser photocoagulation for proliferative disease while diabetic macular edema is treated by focal or a grid laser treatment and intraocular anti-VEGF agents and steroids. Current DR therapies are associated with inconvenient delivery (laser surgery, frequent intraocular injections) and unpleasant side-effects (steroid- induced glaucoma and cataract). Development of an oral drug that slows or prevents the DR progression without destroying photoreceptors by laser or without frequent intravitreal injections is of high significance. Photoreceptor contribution to retinal pathology in DR seems to be caused by hyperglycemia-induced excessive generation of superoxide followed by activation of pro-inflammatory markers. The energy demand, oxygen consumption, and superoxide generation in photoreceptors are far greater in darkness than in light due to the biology of the phototransduction cascade. Our underlying theory is that partial activation of the phototransduction cascade in the dark-adapted diabetic retina may decrease the metabolic load, lessen oxygen consumption, reduce superoxide generation, and inhibit retinal inflammation. Partial activation of phototransduction in the dark can be accomplished by reducing the concentration of visual chromophore, 11- cis-retinal. We recently discovered and characterized several novel classes of Retinol-Binding Protein 4 (RBP4) antagonists. This pilot study will seek to identify a group of RBP4 antagonists capable of partial activation of the visual phototransduction cascade in dark-adapted eyes. We will characterize the optimized RBP4 antagonists from different structural classes for the ability to reduce the visual chromophore concentration in mouse dark-adapted eyes (Specific Aim 1), and perform comprehensive in vivo evaluation of the selected set of analogs in relevant animal models (Specific Aim 2).